Serotonin-to-dopamine transporter ratios in Parkinson disease

Abstract

Objective: To investigate whether a serotonin-to-dopamine terminal ratio is related to the appearance of dyskinesias in patients with Parkinson disease (PD).Methods: Twenty-eight patients with idiopathic PD (17 with levodopa-induced dyskinesias [LIDs], 11 without dyskinesias) and 12 age-matched healthy controls were studied with PET and 5[11 C]-3-amino-4-(2-dimethylaminomethylphenyl-sulfanyl)-benzonitrile ( 11 C-DASB) and with SPECT and [ 123 I]N-w-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)nortropane ( 123 I-ioflupane), which are in vivo specific markers of the serotonin and dopamine transporters' availability, respectively. We have employed a simplified reference tissue model for the quantification of 11 C-DASB, whereas a semiquantification approach was used for 123 I-ioflupane data. We calculated 11 C-DASB binding to 123 I-ioflupane uptake ratios for the caudate and the putamen.Results: Patients with PD showed striatal decreases in 11 C-DASB binding potential (p , 0.01) and in 123 I-ioflupane mean uptake (p , 0.001) compared to controls. The mean 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen was 0.779 (increased by 75.8% of the controls' mean) for the nondyskinetic group and 0.901 (increased by 103.4% of the controls' mean) for the patients with dyskinesias. There was a statistically significant difference (p , 0.001) in 11 C-DASB binding to 123 I-ioflupane uptake ratio in the putamen between the group of patients with and without dyskinesias. Higher 11 C-DASB to 123 I-ioflupane binding ratios correlated with longer disease duration for the 28 patients with PD (r 5 0.52; p , 0.01).Conclusions: Serotonin-to-dopamine transporter binding ratio increases as PD progresses and patients experience LIDs. Our findings suggest that, when the dopaminergic innervation in the striatum is critically low, the serotonergic system plays an important role in development of LIDs. Studies in the animal model of Parkinson disease (PD)1 as well as in humans 2-4 have indicated that degeneration of dopaminergic presynaptic terminals in the striatum is critical in the development of L-dopa-induced dyskinesias (LIDs). Due to the progressive degeneration, striatal dopaminergic terminals lose their dopamine storage capacity and the ability to maintain a stable dopamine release rate in the synapse. 5 Serotonergic terminals have been found capable of converting exogenous levodopa into dopamine, store it in synaptic vesicles, and release it in an activity-dependent manner. [6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model 10-12 and PD.13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

“…In agreement with previous findings,48 DAT binding measurements did not differ between PDSK and PD, thus further supporting that LIDs expression does not rely on the dopaminergic tone per se, but rather on compensatory attempts and derangements of different aminergic pathways and possibly on a disproportion in their degeneration 5, 38, 39. This finding, together with the usual young disease onset of dyskinetic patients2, might support the notion of a neuroprotective effect of the cholinergic system on nigrostriatal dopamine‐containing neurons 49, 50, 51.…”

“…The serotonin (5‐HT) system has received much attention as 5‐HT fibers can convert levodopa into dopamine without the regulatory mechanisms required for dopaminergic transmission, resulting in dysregulated, nonphysiologic dopamine release, which may underlie LIDs 38, 39. Acetylcholine, nicotine, and nicotinic receptor agonists (i.e., epibatidine) can significantly increase 5‐HT release from striatal synaptosomes, an effect that was blocked by mecamylamine, a noncompetitive nicotinic receptor antagonist 40.…”

“…Indeed, in PD the caudate nucleus presents the combination of mild to moderate dopamine loss and scarce serotonergic fibers. Postmortem as well as recent in vivo molecular imaging studies have suggested a more marked serotonin deficiency in the caudate nucleus than in the putamen 38, 39, 43. A sustained cholinergic signaling in the caudate nucleus would therefore be necessary to maintain a levodopa‐derived dopamine release from the remaining striatal serotonin neurons.…”

Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson's Disease

“…[118] Furthermore, an increased serotonin-to-dopamine transporter binding ratio accelerates PD progression. [119] Several clinically available drugs have been assessed recently in this context [Table 1]. …”

The serotonergic system in Parkinson’s patients with dyskinesia: evidence from imaging studies

“…We have extensively investigated the pre-synaptic role of serotonergic terminals in the development of LIDs (Politis et al 2014; Roussakis et al 2016; Smith et al 2015) and in Parkinson’s disease (Politis 2010; Politis et al 2010, 2011). …”